Download Chapater 12 - IND/NDA/ANDA/AADA

Chapater 12 - IND/NDA/ANDA/AADA
Investigational New Drug (IND) Application
After completing preclinical testing, the company files an IND with FDA to begin to test the drug in Human.
INDA (Investigational New Drug Application) is the means through which sponsor (usually the manufacturer
or potential marketer) obtain a legal status to call its new investigational molecule as new drug. The IND is
not an application for marketing approval. Rather, it is a request for an exemption from the Federal
regulations that prohibits an unapproved drug from being shipped in interstate commerce. Current Federal
law requires that a drug be the subject of an approved marketing application before it is transported or
distributed across state lines. Because a sponsor will probably want to ship the investigational drug to
clinical investigators in many states, it must seek an exemption from that legal requirement. The IND is the
means through which the sponsor technically obtains this exemption from the FDA; however, its main
purpose is to detail the data that provide documentation that it is indeed reasonable to proceed with
certain human trials with the drug. During the IND review process, the medical reviewer evaluates the
clinical trial protocol to determine:
l
if the participants will be protected from unnecessary risks; and
l
if the study design will provide data relevant to the safety and effectiveness of the drug.
The IND becomes effective if FDA does not disapprove it within 30 days. The IND shows results of previous
experiments, how, where and by whom the new studies will be conducted; the chemical structure of the
compound; how it is thought to work in the body; any toxic effects found in the animal studies; and how the
compound is manufactured. In addition, the IND must be reviewed and approved by the Institutional
Review Board where the studies will be conducted, and progress reports on clinical trials must be submitted
at least annually to FDA.
The requirements for the format and content of the IND application, as well as the requirement governing
the use of the IND application, are provided in Title 21 of the CFR, Section 312.
Main components of an IND are:
l
Description of the drug substance
l
Chemistry, manufacturing and control information
l
All known pre-clinical information
l
Any previous human study reports
l
Investigator's brochure
l
Clinical development plan
l
Protocol and investigator list submission for the phase I clinical trial.
Each time a new study protocol or new study site is initiated or investigator added to an ongoing protocol,
the IND must be amended. Protocol amendments also require an amendment to the IND. The FDA has 30
days to respond to the sponsor's IND. Refer to 21CFR 312.23 for specifics regarding the IND format and
content.
Categories of IND
Commercial and Non Commercial (Research)
"Commercial INDs" are applications that are submitted primarily by companies whose ultimate goal is to
© Copyright Catalyst Clinical Services Pvt. Ltd.
IND Review Flow Chart
Applicant (Drug Sponsor)
IND
Review by CDER
Pharmacology/
Toxicology
Chemistry
Medical
Statistical
Sponsor Submits
New Data
Safety Review
Safety
Acceptable for
Study to
Proceed?
Clinical
Hold
Decision
No
No
Yes
Yes
Notify Sponsor
Complete Reviews
Reviews
Complete and
Acceptable?
No
Sponsor Notified
of Deficiencies
Yes
No Deficiencies
Study Ongoing*
*While Sponsor answers any deficiencies
Ref. www.fda.gov/cder/handbook
© Copyright Catalyst Clinical Services Pvt. Ltd.
obtain marketing approval for a new product. However, there is another class of filings broadly known as
"Non-commercial" INDs. The vast majority of INDs are, in fact, filed for noncommercial research. These
types of INDs include "Investigator INDs," "Emergency Use INDs," and "Treatment INDs."
l
Investigator IND is submitted by a physician who both initiates and conducts an investigation, and
under whose immediate direction the investigational drug is administered or dispensed. A physician
might submit a research IND to propose studying an unapproved drug, or an approved product for a
new indication or in a new patient population. In this case, the physician is both the sponsor and
investigator. Usually the investigator will cross-reference the original sponsor companies IND for the
pre clinical and clinical information.
l
Emergency Use IND: The FDA can authorize immediate dispensing of a non-approved drug in a life-
threatening situation when no standard acceptable therapy is available and there is not enough time
to obtain IRB approval. This may also be referred to as "compassionate use" IND.
l
Treatment IND: Non-approved drugs showing promise in clinical testing for treatment of serious or life-
threatening conditions are made available while the final clinical work and the FDA review is still
ongoing. FDA will permit an investigational drug to be used under a treatment IND if there is
preliminary evidence of drug efficacy and the drug is intended to treat a serious or life-threatening
disease, or if there is no comparable alternative drug or therapy available to treat that stage of the
disease in the intended patient population. In addition, these patients are not eligible to be in the
definitive clinical trials, which must be well underway, if not almost finished. An immediately lifethreatening disease means a stage of a disease in which there is a reasonable likelihood that death will
occur within a matter of months or in which premature death is likely without early treatment. For
e.g., advanced cases of AIDS, herpes simplex encephalitis, and subarachnoid hemorrhage are all
considered to be immediately life-threatening diseases. Treatment INDs are made available to
patients before general marketing begins, typically during Phase 3 studies. Treatment INDs also allow
FDA to obtain additional data on the drug's safety.
The IND application (FDA 1571) must contain information in three broad areas:
l
Animal Pharmacology and Toxicology Studies: Preclinical data to permit an assessment as to whether
the product is reasonably safe for initial testing in humans. Also included are any previous experiences
with the drug in humans (often foreign use).
l
Manufacturing Information: Information pertaining to the composition, manufacturer, stability, and
controls used for manufacturing the drug substance and the drug product. This information is
assessed to ensure that the company can adequately produce and supply consistent batches of the
drug.
l
Clinical Protocols and Investigator Information: Detailed protocols for proposed clinical studies to
assess whether the initial-phase trials will expose subjects to unnecessary risks. Also, information on
the qualifications of clinical investigators professionals (generally physicians) who oversee the
administration of the experimental compound to assess whether they are qualified to fulfill their
clinical trial duties. Finally, commitments to obtain informed consent from the research subjects, to
obtain review of the study by an institutional review board (IRB), and to adhere to the investigational
new drug regulations.
© Copyright Catalyst Clinical Services Pvt. Ltd.
New Drug Application (NDA)
An NDA is an application submitted to the United States FDA for permission to market a new drug product
in the United States. To obtain this permission, a drug manufacturer/sponsor submits in an NDA nonclinical (animal) and clinical (human) test data and analyses, drug information, and descriptions of
manufacturing procedures.
Fundamentals of NDA Submissions
Although the quantity of information and data submitted in NDAs can vary significantly, the components of
NDAs are more uniform. The components of any NDA are, in part, a function of the nature of the subject
drug and the information available to the applicant at the time of submission. NDAs can consist of as many
as 15 different sections:
l
Index;
l
Summary;
l
Chemistry, Manufacturing, and Control;
l
Samples, Methods Validation Package, and Labeling;
l
Non-clinical Pharmacology and Toxicology;
l
Human Pharmacokinetics and Bioavailability;
l
Microbiology (for anti-microbial drugs only);
l
Clinical Data;
l
Safety Update Report (typically submitted 120 days after the NDA's submission);
l
Statistical;
l
Case Report Tabulations;
l
Case Report Forms;
l
Patent Information;
l
Patent Certification; and
l
Other Information.
NDA Content and Format Requirements
The NDA must provide all relevant data and information that a sponsor has collected during the product's
research and development though the exact requirements are a function of the nature of a specific drug.
The FDA has numerous guidelines that relate to NDA content and format issues which can be found on its
website. (www.fda.gov/cder/regulatory/applications).
NDA Classifications
New Drug Applications are being classified by FDA with a code that reflects both the type of drug being
submitted and its intended uses. The numbers 1 through 7 are used to describe the type of drug:
1. New Molecular Entity;
2. New Salt of Previously Approved Drug (not a new molecular entity);
3. New Formulation of Previously Approved Drug (not a new salt or a new molecular entity);
4. New Combination of Two or More Drugs;
5. Already Marketed Drug Product - Duplication (i.e., new manufacturer);
6. New Indication (claim) for Already Marketed Drug (includes switch in marketing status from
prescription to OTC);
© Copyright Catalyst Clinical Services Pvt. Ltd.
NDA Review Flow Chart
Applicant (Drug Sponsor)
NDA
No
Application
Fileable?
Refuse to File
Letter Issued
Yes
Review by CDER
Medical
Biopharmaceutical
Pharmacology
Statistical
Chemistry
Microbiology
Advisory
Committee
Meeting
Meetings with
Sponsor
Reviews
Complete and
Acceptable?
Sponsor Revises
No
(1) Labeling in this context means
official instruction for use
(2) Manufacturing sites and sites where
significant clinical trials are performed
© Copyright Catalyst Clinical Services Pvt. Ltd.
Additional Info or Revisions
Requested or Submitted
(Amendment)
Yes
Yes
Labeling
Review
Aceptable?
(1)
No
Yes
Inspection
of Sites
Aceptable?
(2)
No
Pending
Satisfactory
Results
NDA Action
Ref. www.fda.gov/cder/handbook
7. Already Marketed Drug Product - No Previously Approved NDA.
The following letter codes describe the review priority of the drug:
S- Standard review for drugs similar to currently available drugs.
P- Priority review for drugs that represent significant advances over existing treatments.
After a New Drug Application (NDA) is received by the agency, it undergoes a technical screening generally
referred to as a completeness review. This evaluation ensures that sufficient data and information have been
submitted in each area to justify "filing" the application—that is, justifying initiating FDA formal review of the
NDA.
At the conclusion of FDA review of an NDA, there are three possible action letters that can be sent to the
sponsor:
l
Not Approvable letter lists the deficiencies in the application and explains why the application cannot be
approved.
l
Approvable letter signals that, ultimately, the drug can be approved. Lists minor deficiencies that can be
corrected, often involves labeling changes, and possibly requests commitment to do post-approval
studies.
l
Approval letter states that the drug is approved. May follow an approvable letter, but can also be issued
directly.
If the action taken is either an approvable or a not approvable action (as opposed to an approval action), FDA
provides applicants with an opportunity to meet with Agency officials and discuss the deficiencies. The
purpose of the meeting is to discuss what further steps are necessary before the application can be
approved.
The goals of the NDA are to provide enough information to permit FDA reviewer to reach the following key
decisions:
R
Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug
outweigh the risks.
R
Whether the drug's proposed labeling (package insert) is appropriate, and what it should contain.
R
Whether the methods used in manufacturing the drug and the controls used to maintain the drug's
quality are adequate to preserve the drug's identity, strength, quality, and purity.
© Copyright Catalyst Clinical Services Pvt. Ltd.
Abbreviated New Drug Application (ANDA) and Abbreviated Antibiotic Drug Application (AADA)
An Abbreviated New Drug Application (ANDA) and Abbreviated Antibiotic Drug Application (AADA) is
submitted to FDA's Center for Drug Evaluation and Research, Office of Generic Drugs to obtain the approval
to market a generic drug product. It contains data which when, provides for the review and ultimate once
approved, an applicant may manufacture and market the generic drug product to provide a safe, effective,
low cost alternative.
.
Generic drug applications are termed "abbreviated" because they are generally not required to include
preclinical (animal) and clinical (human) data to establish safety and effectiveness. Instead, generic
applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same
manner as the innovator drug).
.
Using bioequivalence as the basis for approving generic copies of drug products was established by the
"Drug Price Competition and Patent Term Restoration Act of 1984" also known as the Waxman-Hatch Act.
This Act expedites the availability of less costly generic drugs by permitting FDA to approve applications to
market generic versions of brand-name drugs without conducting costly and duplicative clinical trials A
generic drug product is one that is comparable to an innovator drug product in dosage form, strength, route
of administration, quality, performance characteristics and intended use. All approved products, both
innovator and generic, are listed in FDA's Approved Drug Products with Therapeutic Equivalence
Evaluations (Orange Book).
.
Generic drug application (FDA 356h) reviewers focus on bioequivalence data, chemistry and microbiology
data, requests for plant inspection, and drug labeling information. ANDA must contain sufficient
information to allow a review to be conducted in an efficient and timely manner. If the application is missing
one or more essential components, a Refuse to File letter is issued to the applicant. The letter identifies the
missing component(s) and informs the applicant that the application will not be filed until it is complete.
.
Bioequivalence Review
FDA requires an ANDA applicant to provide information to establish bioequivalency. Such information may
include:
l
formulation comparison for products whose bioavailability is self evident, for e.g., oral solutions,
injectables, or ophthalmic solutions where the formulations are identical;
l
comparative dissolution testing where there is a known correlation between in vitro and in vivo
effects;
l
in vivo bioequivalence testing comparing the rate and extent of absorption of the generic to the
reference product;
l
and for non-classically absorbed products, a head-to-head evaluation of comparative effectiveness
based upon clinical endpoints.
.
If the Bioequivalence Review determines that there are deficiencies in the Bioequivalence portion of the
application, then a Bioequivalence deficiency letter is issued to the applicant. The deficiency letter will
detail the deficiencies and request information and data to resolve the deficiencies. If the review
determines the bioequivalence portion of the application is acceptable, a letter indicating that there are no
further questions at that time will be issued.
.
ANDA/AADA Approval
After the review of all components of an ANDA, an approval or tentative letter may be issued to the
applicant detailing the conditions of the approval and providing them with the ability to market the generic
© Copyright Catalyst Clinical Services Pvt. Ltd.
drug product. If the approval occurs prior to the expiration of any patents or exclusivities accorded to the
reference listed drug product, a tentative approval letter is issued to the applicant which details the
tentative approval of the generic drug product until the patent/exclusivity condition has expired. A
tentative approval does not allow the applicant to market the generic drug product.
.
Note: Although the above ANDA/AADA process is described in context of FDA rules and regulation.
© Copyright Catalyst Clinical Services Pvt. Ltd.